DataSheet_1_Low progesterone receptor levels in high-grade DCIS correlate with HER2 upregulation and the presence of invasive components.docx

ObjectiveIn this study, we investigated pivotal molecular markers in human high-grade breast ductal carcinoma in situ (DCIS). Expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2) was measured among various subtypes (Luminal (Lum) A, LumB HER2-, LumB HER2+, HER2-enriched and triple-negative).
MethodsIn total, 357 DCIS cases were classified into respective subtypes, according to the 2013 St. Gallen guidelines. Each subtype was categorized into three subcategories: “Pure” (those without an invasive component), “W/invasive” (those with an invasive component), and “All” (the entire group of the given subtype). ER and PR expression were registered as intervals. Equivocal HER2 immunohistochemistry (IHC) cases (2+) were further investigated using dual-color in situ hybridization.
ResultsThe majority of patients (71%) were over the age of 50. We discovered no significant differences in the proportion of age between the “Pure” and “W/invasive” groups. There was no significant difference in ER/PR expression between “Pure” luminal subtypes of DCIS and “W/invasive” cases. We compared the HER2 IHC scores of “0”, “1+”, and “2+” among LumA and LumB HER2 subtypes and identified no statistically significant differences between “Pure” and “W/invasive” (p = 0.603). ER and PR expression ≥ 50% cutoff value was present in > 90% of all LumA cases. The incidences of cases with ER expression at cutoff values of < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). The proportion of cases with PR expression < 20% showed significant differences in the various luminal subtypes. In luminal B subtypes, low PR expression (< 20%) was significantly associated with both strong HER2 expression (3+) and the presence of an invasive component (p = 0.0001 and p = 0.0365, respectively).
ConclusionsER and PR expression at ≥ 50% cutoff values were found in more than 90% of LumA cases. Samples with ER < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). Low PR expression in high-grade DCIS was strongly associated with HER2 overexpression (3+) and an invasive component (p = 0.0001 and p = 0.0365, respectively).

研究目的
本研究旨在探究人类高级别乳腺导管原位癌（ductal carcinoma in situ, DCIS）的关键分子标志物。针对不同亚型——管腔（Luminal，Lum）A型、LumB HER2阴性型、LumB HER2阳性型、HER2富集型以及三阴性亚型——检测了雌激素受体（estrogen receptor, ER）、孕激素受体（progesterone receptor, PR）以及人表皮生长因子受体2（human epidermal growth factor receptor 2, HER2）的表达状态。

研究方法
本研究共纳入357例DCIS病例，依据2013年圣加仑（St. Gallen）指南进行亚型分类。每个亚型进一步被划分为三个亚组：‘纯型’（无浸润性成分的病例）、‘伴浸润型’（存在浸润性成分的病例）以及‘全部组’（对应亚型的所有病例）。将ER与PR的表达以区间形式记录。对于免疫组织化学（immunohistochemistry, IHC）检测结果为可疑阳性（2+）的HER2病例，采用双色原位杂交技术进行进一步检测。

研究结果
本研究纳入的患者中，71%的患者年龄超过50岁。‘纯型’与‘伴浸润型’两组的年龄构成比无显著差异。DCIS纯型管腔亚型与伴浸润型病例的ER、PR表达水平无显著差异。在LumA型与LumB型HER2亚型中，对比‘0’‘1+’‘2+’的HER2 IHC评分，发现‘纯型’与‘伴浸润型’之间无统计学差异（p=0.603）。在所有LumA型病例中，ER与PR表达量≥50%截断值的占比超过90%。与其他管腔亚型相比，LumA型中ER表达量<10%和≥50%的病例占比存在显著差异（p<0.0001）。不同管腔亚型间PR表达量<20%的病例占比存在显著差异。在LumB型亚型中，低PR表达（<20%）与强HER2表达（3+）以及浸润性成分的存在均显著相关（分别对应p=0.0001与p=0.0365）。

研究结论
超过90%的LumA型病例的ER与PR表达量达到≥50%的截断值。与其他管腔亚型相比，LumA型中ER表达量<10%和≥50%的病例占比存在显著差异（p<0.0001）。高级别DCIS中的低PR表达与HER2过表达（3+）及浸润性成分的存在密切相关（分别对应p=0.0001与p=0.0365）。